It has been a busy year again for the DISC1 research community, so we invite you to join us once again for a live discussion on Wednesday, 13 January 2010, from 12:00 noon to 1 p.m. (U.S. EST), led by Akira Sawa, Johns Hopkins University, and David Porteous, University of Edinburgh. DISC1 barely needs introduction or justification any longer as a suitable topic for SRF discussion.

DISC1 is now well established as what Tom Insel, Director of the U.S. National Institute of Mental Health, has termed an “edge piece” of psychiatric genetics. Many studies have reported effects of DISC1 genetic variation on a spectrum of psychiatric disorders, including and extending beyond the schizophrenia, bipolar disorder, unipolar depression, and adolescent conduct disorder reported in the original Scottish family with a balanced t(1;11) translocation through which DISC1 was identified. The neurodevelopmental and neurosignaling roles of DISC1 are increasingly well understood through the scaffold function of DISC1, including GSK3β, PCM1, PDE4, NDE1, and NDEL1, to name but some of the currently most interesting and well studied interactors that are illuminating normal and pathogenetic brain processes. (See Brandon et al., 2009; Porteous and Millar, 2009; Jaaro-Peled et al., 2009; and Chubb et al., 2008 for more background and review summaries.)

The focus of this meeting will be as follows:

1. Update on animal models: What are these models telling us about the neurobiology of DISC1? What are the key DISC1-associated behavioral phenotypes? What kinds of criteria, including histological and molecular hallmarks, are most relevant to translational research? What experiments still need to be done? What other models are needed?

2. Update on DISC1 genetics: What is the status on evidence for common risk variants and rare mutations in the DISC1 pathway? What do these tell us about genotype-phenotype relationships? What do they tell us about structure-function relationships?

3. Update on DISC1 signalosome: What underlies the temporal and spatial specificity of DISC1 pathways in brain circuitry, such as isoform disposition, post-translational modifications, and different combinations of protein interactors?

We now invite your comments in advance of the live discussion and look forward to your participation.

To follow up on Atsushi's and Tatiana's comments, I would...
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To follow up on Atsushi's and Tatiana's comments, I would like to suggest we need to start thinking and going beyond the existing cell and mouse DISC1 models that have been focused on neuronal functions of DISC1. It may be a good time to begin developing approaches to address possible glial functions of DISC1 as well. The first available data are promising, but, of course, require further replications and confirmations.

Accumulating evidence suggests that DISC1 plays roles in various aspects of cell behavior, including a role in cell proliferation, neuronal migration, axon growth, and dendritic/spine development during brain development and even in adulthood (Duan et al., 2007; Enomoto et al., 2009; Kamiya et al., 2005; Mao et al., 2009; Meyer and Morris, 2009). These results clearly indicate the importance of the timing of gene targeting for the study of such multifunctional molecules. DISC1 is a protein that interacts with many other molecules. Interestingly, some interactors, such as NDEL1, NDE1, PDE4, and PCM1, were also reported as risk factors for schizophrenia (Burdick et al., 2008; Gurling et al., 2006; Hennah et al., 2007; Kamiya et al., 2008; Millar et al., 2005). Furthermore, genetic association of DISC1 with cognitive function in healthy individuals is also reported (Thomson et al., 2005). Thus, DISC1 may play roles in common molecular mechanisms with other genetic risk factors underlying higher brain functions, such as cognition, which may be disturbed in disease conditions. Nonetheless, it is still unknown which functional aspect of DISC1 directly affects molecular mechanisms underlying this susceptibility. Segregation of specific roles for DISC1 in restricted cell types and brain regions in specific developmental periods may be crucial for addressing DISC1-mediated disease molecular pathways precisely.

A recent study (Crepel et al., 2010) has reported autism in a family with duplication of the DISC1 region. May I ask, has there been any work, or is work planned, on animal models that would allow functional analyses of the effects of increased expression of DISC1?

Response to: 1. Update on animal models: What are these models telling us about the neurobiology of DISC1? What are the key DISC1-associated behavioral phenotypes? What kinds of criteria, including histological and molecular hallmarks, are most relevant to translational research? What experiments still need to be done? What other models are needed?

Accumulating data based on neurobehavioral phenotypes of different Disc1-modified mouse models indicate major commonalities such as
changes in the brain volume and ventricle size; altered density of spines on neurons; hyperactivity; deficient sensorimotor gating; social behavior; immobility in the forced swim test. Pharmacologically, still not many models have been used to probe the efficacy of different antipsychotics or response to psychostimulants. A summary of phenotypes of different Disc1 mouse models could be find in the paper of Shen et al., 2008.

The most recent progress in the Disc1 field is related to the neurodevelopmental part of schizophrenia, and the excellent reviews of Jaaro-Peled et al., 2009 and Brandon et al., 2009 stated clearly that Disc1 plays multiple key roles in brain development.

A very recent paper from Dr. Pletnikov's group (Ayhan et al., 2010) found distinct effects of expression of the mutated Disc1 in prenatal, postnatal, or both stages of development on behavioral phenotypes, changes in monoamines, responses to psychostimulants, brain changes. This is direct confirmation of the Disc1 role in neurodevelopmental processes using mouse models with inducible expression of mutant human Disc1 (hDisc1).

The next step is to create models which could modulate specifically Disc1-protein [X] interaction and elucidate the roles of each Disc1-interacting protein [X] in the psychopathological processes related to schizophrenia, bipolar disorder, autism, and cognitive functions. The modified Disc1-protein [X] could be induced in particular brain regions to find out the input of the impaired Disc1-protein [X] interaction in a brain region-dependent manner.

I am currently at NIMH as visiting scientist. Barbara Lipska and I are planning to examine blood RNA transcripts from two schizophrenia cases with probable stop codons in DISC1. If anyone has other DISC1 mutations please let us know as we can analyze at the same time.

DISC1 is clearly hugely important, acting as a "hub gene"...
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DISC1 is clearly hugely important, acting as a "hub gene" linked to other susceptibility gene products in both bipolar disorder and schizophrenia. A DISC1 interactome was posted on the Polygenic Pathways website in 2007 and has now been updated (based on the work of many in this online discussion). It shows a plethora of susceptibility gene products linked to DISC1 in either one or two steps. This is most evident in schizophrenia, but is also impressive in bipolar disorder.

This updated interactome, specifically in relation to other bipolar and schizophrenia gene candidates, is posted at Polygenic Pathways, where links to the BIOGRID, PSTIING, and HPRD interactomes are also provided.

The interactions are referenced and also derive from the interactions section of Entrez Gene.
For some browsers, the genes should be clickable with links to NCBI genes. A glutamatergic interactome in schizophrenia and bipolar disorder, again implicating DISC1, is also provided.

The overall conclusion is that DISC1 resides at the center of a web of interacting proteins that are crucial to our understanding of these complex disorders.